1. Field of the Invention
This invention relates to compounds useful as kinase inhibitors and methods for their preparation and use.
2. Description of Related Art
Protein kinases (“kinases”) constitute a large family of enzymes that phosphorylate other proteins with adenosine triphosphate (“ATP”) as the phosphate source. They include serine kinases and tyrosine kinases, which phosphorylate hydroxyl groups on serine and tyrosine residues, respectively, on their target proteins. Kinases can also be dual function, meaning that they phosphorylate both serine and tyrosine residues. The target protein can be an enzyme, a membrane channel, or other protein.
Cellular activity is often controlled by an external signaling molecule (e.g., a hormone or a mitogen), whose binding to a cognate receptor at the cell surface stimulates or inhibits various intracellular events. The initial signaling molecule-receptor interaction triggers a signaling cascade, or cell-signaling pathway, of additional protein interactions within the cell, often involving the kinase-mediated phosphorylation of proteins (signal transduction). Thus, at the molecular level, cellular activities are regulated by the phosphorylation (and dephosphorylation) of associated kinases and other proteins such as transcription factors. Cellular activities so regulated include cell growth, cell division, and apoptosis.
Many diseases of unwanted cell proliferation (such as cancer, psoriasis, restenosis) are characterized by disruptions in a signaling cascade, causing cell proliferation to become unchecked. Often, the disruption arises from a single mutation in a protein located upstream in the signal cascade, affecting the regulation of multiple kinases downstream. Thus, inhibition of the affected kinase(s) has been advanced as a basis for the treatment of cancer. Sausville et al., Ann. Rev. Pharmacol. Toxicol. 2003, 43, 199-231, “Signal Transduction-Directed Cancer Treatments”.
The resorcylic acid lactones (“RALs”) are a family of natural products having a 14-member lactone ring incorporating a resorcylic acid residue, an example being hypothemycin:

There exist several disclosures that RALs—and their semi-synthetic or synthetic analogs or derivatives—are kinase inhibitors and therefore are useful for treating diseases characterized by abnormal kinase activity. See, e.g., Giese et al., U.S. Pat. No. 5,795,910 (1998); Chiba et al., US 2004/0224493 A1 (2004); and Santi et al., US 2006/0079494 A1 (2006).
The present invention provides novel compounds—which may be viewed as RAL analogs—that are effective kinase inhibitors and are useful for treating a disease or condition amenable to treatment by inhibition of a kinase.